The NR4A subclass of nuclear receptor (NR) transcription factors (Nurr1, Nur77 and NOR-1) have essential roles in the development, regulation and maintenance of many aspects of mammalian physiology. NR4As are especially abundant in the central nervous system (CNS) and play critical roles in brain development and maintenance. Therapeutics targeting NR4A activity may hold utility in treatment of Parkinson's disease (afflicts 1 million people in the US) and schizophrenia (afflicts >3 million people in the US). The NR4As are also expressed in skeletal muscle, adipose, cardiovascular, kidney and liver tissues, including aberrant expression in inflamed disease tissues, suggesting utility forNR4A modulators to treat inflammation, arthritis, cancer, and metabolic conditions (dysli idemia, obesity, diabetes and cardiovascular disease). However, efforts to probe the ligandability and drugga- bility of the NR4As have been significantly stunted because they are classified as orphan receptors. Thus far, no endogenous (natural) NR4A ligands have been discovered, and it is believed the NR4As function independent of binding ligand. This orphan classification was made in part based on a crystal structure of apoNurr1, which indicates Nurr1 lacks physical space within the conserved ligand biding pocket region used by nonorphan NRs to bind endogenous ligands. Although the apoNurr1 crystal structure shows a collapsed ligandbinding pocket, NMR studies indicate this region is dynamic on the s-ms timescale, suggesting the ability to expand. Our preliminary work using an array of structural and functional approaches shows that Nurr1 can bind an endogenous ligand in its putative LBP and that endogenous ligands can affect Nurr1 function. Our data also indicate that Nurr1 and Nur77 may have different specificities for endogenous ligands. Detailing the structural mechanism and function of endo- genous ligands targeting the NR4As will demonstrate these orphan receptors are indeed ligand regulated and empower others to use these natural chemical tools to explore NR4A function in vivo. We propose a multidisciplinary approach combining structural biology with biochemical, biophysical and cellular assays to determine the ligand specificity, structural and functional effects, and cellula outcomes of endogenous ligands targeting the NR4As. Outcomes from these studies would demonstrate that the NR4As are bone fide ligand-binding receptors. Because NRs with known endogenous ligands are targets of significant number of current FDA approved drugs (estimated at 13% in 2006), this knowledge will stimulate the development of NR4A drug targeting strategies for Parkinson's disease, schizophrenia, and other human health conditions.